The islet in humans with type 2 diabetes (T2DM) is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP), a protein that is co-expressed and secreted with insulin. Human IAPP (hIAPP) has the propensity to form oligomers in solution. These oligomers appear to form in membranes inducing non selective membrane leakage, for example of Ca2+ into cytosol. In studies supported by this grant we established that -cell mass is decreased in humans with T2DM, with increased -cell apoptosis. We reproduced the islet and metabolic phenotype of T2DM in rodents over expressing human IAPP, and documented that the toxic form of IAPP oligomers form intracellularly within the secretory pathway leading to endoplasmic reticulum (ER) stress induced apoptosis as well as organelle (mitochondrial) damage. We have established that -cells in humans with T2DM are also characterized by intracellular formation of toxic hIAPP oligomers, leakage of Ca2+ into cytosol leading to hyperactivation of the Ca2+ sensitive protease calpain. Collectively these characteristics reproduce those in neurodegenerative diseases mediated by proteotoxicity of amyloidogenic proteins (e.g. Alzheimers). In the neurodegenerative diseases there is an increasing appreciation that proteotoxicity by amyloidogenic proteins is mediated in part through disruption of the cellular mechanisms that remove misfolded and aggregated proteins, the ubiquitin/proteosome system and autophagy. In the proposed studies we propose studies to address the following aims. 1) To establish the specific mechanisms by which IAPP oligomers induce -cell apoptosis and dysfunction. 2) To establish if the ubiquitin proteosome system to protect against proteotoxicty is impaired by hIAPP toxic oligomers, and if so through which mechanism(s). 3) To establish if autophagy, the cellular system for removal of toxic oligomers and damaged organelles, is disrupted by hIAPP toxic oligomers, and if so, through which mechanisms. This program of studies would allow us to shed light into the underlying cause of loss of -cells in humans, and to establish a rationale approach to preventing this. PUBLIC HEALTH RELEVANCE: More than 25 million Americans now have Type 2 diabetes. The complications arising from type 2 diabetes (blindness, early death through heart disease, loss of limb, kidney failure) are the single largest cost to the US health system. The present studies are targeted to establish a better understanding of the underlying cause of type 2 diabetes so that more rationale efforts can be used to prevent and treat it.